Dopamine is a hormone and a neurotransmitter present in both vertebrates and invertebrates. Chemically it is a phenethylamine present in the brain and acts as a neurotransmitter which activates specific dopamine receptors (D1-D5). Dopamine has many functions in the brain, including important roles in behavior and cognition, motor activity, motivation and reward, regulation of milk production, sleep, mood, attention, and learning. Dopamine plays a major role in appetite, Sociability, Salience, Behavior disorders, Latent inhibition and creative drive. Dopamine is also involved in regulating prolactin secretion.
Inadequate levels of dopamine trigger symptoms like tremors, rigidity and bradykinesia (slowness of movement). In healthy subjects, neurons produce and release dopamine in the brain and other parts of the body. When the dopamine is released by one neuron, it is received by the receptors of the next neuron. This chain reaction eventually leads to the stimulation of nerves. Various neurological disorders can interfere with dopamine production and cause the dopamine levels in the brain to drop. Abnormal levels of dopamine also cause a number of disorders, some of which are chronically degenerative (like Parkinson's disease).
Dopamine strongly influences both motor and thinking areas of the brain. One type of Dopamine works in the movement and motor system. When levels of dopamine decrease below the “normal range” motor and gross-movement problems set in. Very low levels of Dopamine in the motor areas of the brain are known to produce Parkinson's Disease with symptoms such as: muscle rigidity and stiffness, stooped/unstable posture, loss of balance and coordination, gait (walking pattern) disturbance, slow movements and difficulty with voluntary movements, Small-step gait/walking, aches in muscles, tremors and shaking, fixed, mask-like facial, expression, slow, monotone speech, impairment of fine-motor skills, falling when walking and an impairment in cognitive/intellectual ability
Low levels of dopamine impair the ability to focus on an environment or to “lock on” to tasks, activities, or conversations. Low levels of Dopamine make concentration and focus very difficult and are also associated with Attention-Deficit Hyperactivity Disorder (ADHD).
Dopamine also plays a major role in inhibiting prolactin secretion. Prolactin is a peptide hormone secreted by the lactotroph cells in the pituitary gland. Prolactin plays a major role in inducing lactation and sexual gratification (which is caused by low levels for dopamine. Adequate levels of dopamine are required for sexual arousal). Dopamine serves as the major prolactin-inhibiting factor and is secreted into portal blood by hypothalamic neurons, binds to receptors on lactotrophs, and inhibits both the synthesis and secretion of prolactin. Increased levels of prolactin have many ill effects like infertility, polycystic ovary syndrome (PCOS), headaches, reduced sex drive and vision problems. High prolactin levels are caused due to many factors including physical and mental stress. Hence a dopaminergic compound (one that increases dopamine levels) will play a key role in regulating (limiting) the levels of prolactin thereby managing the various effects of high levels of prolactin.
It is found that chronic and strenuous exercise as practiced by athletes, body builders and sportsman also leads to an increase in prolactin level. This increased prolactin decreases their sexual libido and induces sexual dysfunction. Therefore dopaminergic agents can be used for decreasing the levels of prolactin and thereby eliminating the side effects by maintaining this hormone within physiological limits.
Dopaminergic agents can be used as a muscle relaxant as it inhibits the excitation caused by acetylcholine. Therefore the Dopaminergic substance of this invention can be used as a muscle relaxant in exercise physiology, anesthesia and in case of muscle spasms.
One of the major effects of low levels of dopamine is Movement Disorders. Movement disorders are a group of diseases and syndromes affecting the ability to produce and control movement. To produce any form of movement even simple motions requires the coordination and action of a complex network of signals. Disruption of any portion of this system can cause a person to produce movements that are too weak, too forceful, too uncoordinated, or too poorly controlled for the task at hand. Unwanted movements may occur at rest or intentional movements may become impossible. Such conditions are called movement disorders.
In some cases, the abnormal movements are the only symptoms of low levels of dopamine. Disorders causing abnormal movements include: Parkinson's disease, Parkinsonism caused by drugs or poisons, Parkinson-plus syndromes (progressive supranuclear palsy, multiple system atrophy, and cortical-basal ganglionic degeneration).
These disorders are caused due to a lack or excess of the neurotransmitter Dopamine. Drug therapy can help compensate for some imbalances of the basal ganglionic circuit. Acetylcholine is an excitatory chemical that helps regulate dopamine in the brain. In the body, acetylcholine released at nerve endings causes muscle contraction.
Parkinson's is a progressive degenerative disease, which destroys dopamine-producing cells and leads to a problem in coordinated movement. It is characterized by tremor, rigidity, Akinesia and postural instability. The main biochemical abnormality is the depletion in Dopamine and which causes an imbalance between acetylcholine and dopamine. Causes of Parkinson's are not known clearly. There is weak hereditary link in few cases. It is also caused by an environmental toxin MPTP (Methyl phenyl tetra-hydro pyridine), which is used as a pesticide.
Parkinson's disease is usually a disorder of the elderly occurring after the age of 65. It is caused by the death of a group of nerve cells in the brain called the “Substantia Nigra” or black substance because they look dark in appearance. The nerve process from these cells normally extends up to another area of brain called the striatum, where they make connections and release a chemical called Dopamine as their Neurotransmitter.
The Substantia Nigra and the striatum help to control movement, including our ability to initiate movement. With the loss of the Nigrostriatal pathway, the Parkinson's patient has extreme difficulty in performing such acts like getting out of a chair and starting to walk. They also experience increased tremor and rigid muscles.
Current methods of treatment for dopamine related diseases (eg: Parkinson's and diseases related to low levels of dopamine) include:
L-Dopa (Dihydroxy Phenyl Alanine)
Since the cause of Parkinson's disease is a loss of Dopamine releasing nerve cells, one approach to treating this disorder is to restore the levels of Dopamine in the brain. Dopamine will not pass from the blood into the brain. Within nerve cells, dopamine is produced by a series of chemical reactions catalyzed by enzymes. The last stage in the sequence is the formation of dopamine from the amino acid L-Dopa. L-Dopa easily crosses into the brain from blood. The most popular and effective treatment for Parkinson's is the administration of L-Dopa in tablet form.
L-Dopa gets into blood stream and passes into brain. In the brain Dopa decarboxylase converts this into Dopamine. L-Dopa produces a very marked improvement in general movement, facial expression and body posture. However, it has very poor effect on tremor, swallowing, balance and the slow initiation of movements.
Combining Other Drugs with L-Dopa
The enzyme Dopa Decarboxylase that converts L-Dopa to Dopamine exists in blood and body tissues. Therefore, L-Dopa degrades in the serum to the extent of 90%. This is blocked by inhibiting this enzyme by other drugs like Carbidopa and Benseraside. These are combined with L-Dopa to increase its brain availability. Carbidopa and Benseraside do not pass into the brain.
Tolcapone and Entacalpone
L-Dopa is also destroyed by another enzyme COMT (Catechol O-Methyl Transferase). These drugs inhibit COMPT and make L-Dopa available to brain. But these drugs have long term problem with L-Dopa. On long term administration of L-Dopa, patients may experience fluctuations in its effect. There may be greater delay in the onset of action and drug action period may get shortened. Patients also experience on off periods. This implies that the patients may function perfectly well for long hours after the drug administration and they might find that the effect of the drug stops abruptly.
Side effects of L-Dopa: Most patients feel nausea; prolonged use of this can induce Schizophrenia, especially hallucinations and disturbed sleep. Continued use also leads to slow and involuntary movements.
MAO Inhibitions (Monoamine Oxidase)
An alternative to increasing the formation of dopamine in the brain is by administering L-Dopa to decrease the breakdown of dopamine. Dopamine is broken down by an enzyme Monoamine Oxidase (MAO), particularly MAO-B. Deprenyl is a MAO-B inhibiting.
Receptor Agonists
It is possible to compensate for the loss of Dopamine by using drugs which act directly on Dopamine receptors. Drugs like Bromocriptine, Lisuride are Receptor Agonists. They stimulate the receptors which respond to dopamine and act as replacements for the Dopamine normally released by the Nigrostriatal neurons. These drugs induce a range of involuntarily movements and act on dopamine receptors in the pituitary gland, a part of the brain, which controls many important hormone secretions. The side effects of the activation of Dopamine receptors to suppresses the release of the hormone prolactin are infertility and menstrual disorders.
Anticholinergic Drugs
Within the striatum of the brain, both dopamine and Acetylcholine are neurotransmitters. Dopamine causes inhibition of nerve cells while acetylcholine causes their excitation. When the brain loses Dopamine cells, the activity of acetylcholine is intact. Therefore one strategy is to reduce acetylcholine and balance its effect along with the effect of Dopamine. Anticholinergic drugs are more effective in reducing tremors, although they have no effect on muscular rigidity and difficulty of movement. These drugs have many side effects like dry mouth, blurred vision, constipation, difficulty in urination etc.
U.S. Pat. No. 4,880,816 describes a compound where dopamine is chemically combined to another molecule DHC, particularly of a trigonelline which has blood brain barrier penetration property. Here, DHC compounds acts as an adjunct to dopamine to cross the blood brain barrier and gets broken and eliminated. Thus, it does not define any dopaminergic action for trigonelline.
Current therapy targets symptomatic relief and no agent is capable of inhibiting neuronal degeneration. There is urgent need for a kinder and gentler therapy for long-term management with minimal side effect and with optimum efficiency. The present invention addresses this urgent need for a Dopaminergic product, which can be effectively utilized for the management of diseases associated with the lack of dopamine including Parkinson's disease.
A major disadvantage of anti-psychotic drugs is their blocking the D2 receptor of dopamine. Thus these drugs lead to the side effect of movement disorders linked to blockage of dopamine receptor D2 in the brain. Hence a dopaminergic agent would be the answer to the immobility caused as a side effect of anti-psychotic drugs.